Surgical techniques can only be performed after the highly sensitive nerve endings in the skin are anesthetized. Anesthetic agents are pharmacologically active agents that block nerve impulses conduction in sensory and motor nerve fibers when applied in therapeutically effective amounts. Their action is reversible, their use being followed by the complete recovery in nerve function with no evidence of structural damage to nerve fibers or cells.
To be effective, a topical anesthetic should contain sufficient concentration of the active agent to produce an anesthetic effect, it should penetrate intact skin sufficiently to deliver a therapeutic dose, it should exhibit a rapid onset of anesthetic action and have a prolonged anesthetic effect. Potency of anesthetics in clinical situations depends on both their ability to reach the nerve fibers and their intrinsic blocking activities. Factors such as nerve penetration, vascular absorption, and local tissue binding are all of them determinants for anesthetic potency.
Local anesthetics are traditionally injected into the desired site with a syringe. Most formulations of local anesthetics are aqueous solutions designed for injection into tissue, around nerves, or into the epidural spaces. The use of syringe is disadvantageous because the needle itself causes pain on penetration, the volume of anesthetic dissolution can cause stretching at the site (also causing pain), and furthermore preservatives contained in the aqueous dissolution can cause stinging at the wound site. Pain relief is especially important in the area of pediatrics, where even minimal pain may result in an anxious and uncooperative patient.
It is known the use of topical anesthetics. Transdermal delivery is advantageous over intravenous delivery because the former avoids risks associated with parenteral treatment and eliminates gastrointestinal adverse effects due to pharmaceutical active ingredients, preservatives, etc. However, the use of transdermal anesthetics (i.e. through the skin) is often problematic, and fluid and in gel compositions have often proven unsuccessful.
The amide of formula (I), known as lidocaine, has a melting point of 68-69° C. and it is the most commonly used local anesthetic, especially in the form of aqueous dissolutions of its hydrochloride, which are administered intravenously or topically, as jelly, ointment or spray (cf. U.S. Pat. No. 2,441,498). Unfortunately, when administered topically, these formulations are not effectively absorbed transdermally, but only through mucosal surfaces.

The amide of formula (II), known as prilocaine, is a local anesthetic agent which takes the form of crystalline needles having a melting point of 37-38° C. (cf. GB 839.943-A). Its hydrochloride is crystallized from ethanol and isopropyl ether and it is readily soluble in water. Unfortunately, methemoglobinaemia and cyanosis appear to occur more frequently with prilocaine than with other local anesthetics. Methemoglobinaemia is a disease state of the erythrocyte consisting in the formation of oxidized iron compound in the heme protein of the erythrocyte. Symptoms usually occur when doses of prilocaine hydrochloride exceed about 8 mg per kg body-weight although the very young may be more susceptible. This fact severely limits the size of the area to be anesthetized.
Enhancement of drug absorption through the skin has been a challenge for researchers for many years. Research has been also focused on finding effective topical formulations of an anesthetic which provide a rapid onset and a long duration of anesthesia. When applied onto intact skin, currently available topically used anesthetic preparations are generally ineffective or only partially effective.
One approach to the prolongation of anesthesia involves the combination of topical anesthetics with a vasoconstrictor, but also involves considerable adverse side effects. Another approach involves the combination of several anesthetic agents and different topical excipients (cf. e.g. EP 43.738-A, WO 9633706-A). In fact, at present, the most successful commercially available preparation for dermal anesthesia is the lidocaine-prilocaine cream named EMLA (a registered trademark in some countries) of Astra Lakemedel AB, Sweden (cf. U.S. Pat. No. 4,562,060). In some clinical tests, EMLA cream has been found preferable to lidocaine or to ethylchoride. EMLA is an oil-in-water emulsion in which the organic phase is an eutectic mixture of lidocaine and prilocaine bases (2.5% and 2.5% by weight) in water which is thickened with carbomer (Carbopol®). An eutectic mixture has a melting point lower than the one of any of its ingredients. EMLA cream is applied as a thick layer under an occlusive or semiocclusive dressing for inducing a rapid absorption through the skin.
A major inconvenience of EMLA is that its onset time for anesthesia is relatively long, approximately one hour or more. This onset time is not very practical for several clinical procedures. For more invasive procedures such as split skin graft harvesting, EMLA has to be applied at least two hours prior to surgical operation. Such delay is a problem for both patients and for medical staff, particularly in the area of pediatrics. Moreover, EMLA is formulated at pH 9.0 to incorporate the anesthetic agents in base form. The skin, which has an acidic pH (5 to about 5.5) is sensitive to such a high basic pH and significant skin irritation can occur. Dermal application of EMLA may cause a transient, local blanching followed by a transient, local redness or erythema. Another disadvantage of EMLA is that for deep penetrative effect it is necessary that the cream is applied under occlusive dressing.
There have been several attempts trying to improve EMLA cream. One example are topical anesthetic compositions which additionally include a vasodilator. A formulation including lidocaine base, prilocaine hydrochloride, dibucaine, a vasodilator and carrier is described in the patent application WO 01/54679-A. Another example is the topical anesthetic composition comprising an eutectic mixture of lidocaine and prilocaine in a lipophilic base described in the U.S. Pat. No. 5,993,836. It has been reported that this anesthetic formulation has significantly more rapid onset than similar transdermal anesthetics, such as EMLA cream.
Tetracaine hydrochloride (amethocaine) is a local anesthetic of the ester type with formula (III) (cf. U.S. Pat. No. 1.889.645). There are many topical formulations in the market containing tetracaine hydrochloride, one of them is AMETOP of T.J. Smith & Nephew Limited, England (cf. GB 2.258.397-A) which contains 40 mg of active ingredient (4%, w/w), an aqueous gelling agent and a pharmaceutically acceptable salt.
Thus, it appears to be highly desirable to have a topical anesthetic composition which provides a rapid and deep anesthesia, with a high concentration on skin. In particular, it would be desirable to have a topical anesthetic with the benefits of lidocaine and prilocaine, but free of the above-described limitations associated therewith.